Principle of Pharmacology

Pharmacokinetics By

Dr.Mahendra Y. Sawant
drmys879@yahoo.co.in
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Pharmacokinetics
The study of drug movement into, within and out of the body, which includes absorption, distribution and elimination.
Absorption Transfer of drug from site of administration to systemic circulation Transfer of drug from systemic circulation to tissues Action on the drug by the body by enzymes(in liver) Removal of drug from the body Excretion Metabolism

Distribution Metabolism Elimination -

Site of action Pharmacological effects AR A+R

Other storage tissues AT A+T

plasma
Drug (A) Administration Absorption

Distribution Unchanged A Excretion Metabolism A

Free drug [A] Distribution

Systemic circulation

A+P AP Plasma protein-bound drug (AP) Protein-drug complex

Drug metabolite (A)

90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100

[Drug]

Drug 1 Physical Properties Drug 2

Structure Lipid solubility Ionization state

Time (h)
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Mechanisms of drug transport Drug administration Drug absorption Drug distribution Drug elimination excretion

DRUG

DRUG

DRUG

DRUG

PHARMACOLOGICAL EFFECTS
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Mechanisms of Drug Transport

1. Passive diffusion
a. Passive diffusion of non-electrolytes b. Passive diffusion of electrolytes

2. Filtration 3. Carrier-mediated transport

a. Active transport b. Facilitated diffusion

4. Receptor-mediated endocytosis 5. Ion-pair transport

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Mechanisms of Drug Transport

1. Passive diffusion Low molecular weight drugs that are both water and lipid soluble dissolve in membrane and cross to the other side. Primary means by which drugs cross membranes

Mechanisms of Drug Transport

1. Passive diffusion
Compartment 1
A A A A A A A A A A A A

Compartment 1
A A A A

Membrane
A A A

Membrane
A A A A A

Compartment 2

Compartment 2

Driving force: the concentration gradient across the membrane

Mechanisms of Drug Transport

1. Passive diffusion
1) Passive diffusion of non-electrolytes
2) Passive diffusion of electrolytes

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Mechanisms of Drug Transport

1. Passive diffusion
1) Passive diffusion of non-electrolytes
Lipid-water partition coefficient (Kp) Kp can be measured. Kp = [drug] in lipid phase/[drug] in aqueous phase. If the drug is more soluble in the lipid, Kp is higher. If the drug is more soluble in the aqueous phase, Kp will be lower. The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases.

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Mechanisms of Drug Transport

1. Passive diffusion
1) Passive diffusion of non-electrolytes

The higher the Kp, the more lipid soluble, the faster the rate of transfer across biological membranes

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Mechanisms of Drug Transport

1. Passive diffusion
2) Passive diffusion of electrolytes
Electrolytes: tend to ionize in physiological solutions. Two main categories weak acids and weak bases. Weak acids: HA H+ + AWeak bases: BH+ B + H+

Most drugs are either weak acids or weak bases.

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Mechanisms of Drug Transport

1. Passive diffusion
2) Passive diffusion of electrolytes
Only the unionized forms of the drug or the uncharged drug can pass through or across the membranes by passive diffusion.

By controlling the pH of the solution and/or the pKa of the drug, you can control the rate at which the drug is transferred

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Mechanisms of Drug Transport

2. Filtration - Passage of molecules through pores or porous structures.
The rate of filtration a. Driving force: The pressure gradient in both sides. a. The size of the compound relative to the size of the pore.
i. Smaller compound transfer rapidly ii. Larger compound retained iii. Intermediate compound barrier

Lipid soluble passive diffusion Water soluble filtration

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Mechanisms of Drug Transport

2. Filtration
The rate of filtration:

In biological systems: Filtration is the transfer of drug across membrane

through the pores or through the spaces between cells

a. Capillary endothelial membranes b. Renal glomerulus

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Mechanisms of Drug Transport

2. Filtration
Interstitial fluid
Capillary endothelium cells

Blood

Interstitial fluid
Most substances (lipid-soluble or not) cross the capillary wall very fast Lipid soluble and unionized filtration and passive diffusion at the same time
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Mechanisms of Drug Transport

3. Carrier-mediated transport
1) Active transport 2) Facilitated diffusion

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Mechanisms of Drug Transport

3. Carrier-mediated transport
1) Active transport
a. Carrier or receptor-mediated Reversible binding Resemble with endogenous substances that are normal substances for that particular transport system (sugars, amino acids) Selectivity - not for all the drugs Energy-dependent - ATP hydrolysis One-way process against drug concentration gradient - drug accumulation

b. c. d.

Drug

Carrier Receptor Membrane

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Mechanisms of Drug Transport

3. Carrier-mediated transport
2) Facilitated diffusion
a. b. c. d. e. Carrier or receptor-mediated Selectivity It can be saturated Does not require ATP concentration gradient Bi-directional no drug accumulation

Drug

Carrier Receptor Membrane

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Mechanisms of Drug Transport

4. Receptor-mediated endocytosis
- more specific uptake process

Drugs (peptide hormones, growth factors, antibodies, et al) bind to their receptors on the cell surface in coated pits, and then the ligand and receptors are internalized, forming endosomes.
Receptor-ligand complex may take four different pathways:

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Mechanisms of Drug Transport

5. Ion-pair transport
Highly ionized
+ + _ _ + _ _

Passive diffusion
+

Carrier

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Absorption of Drugs
Transfer of drug from the site of administration to the systemic circulation
1. 2. 3. 4. Sites of absorption through the GI tract Factors that modify absorption in the GI tract Bioavailability Other sites of drug administration/absorption

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Absorption of Drugs
1. Sites of absorption through the GI tract

1) 2) 3) 4)

Mouth Stomach Small intestine Large intestine

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Absorption of Drugs
1. Sites of absorption through the GI tract
1) Mouth:
a. Small amount of surface area but good blood flow best for potent drugs.

b. Transfer by passive diffusion good for lipid soluble drugs.

c.

pH = 6. Weak base drugs have better absorption.

Nicotine pKa 8.5 pH Ionization Absorption Mouth 6 more 4 times faster GI tract 1-5 less

d. Can bypass first pass effect.

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Absorption of Drugs
1. Sites of absorption through the GI tract 2) Stomach:
a. Moderate surface area more than mouth, less than small intestine.
b. Good blood supply.

c. Drugs absorbed in the stomach will experience first pass effect.

d. Transfer by passive diffusion.

e. Low pH (1-2) ionization - Drugs that are weak acids will be absorbed better than weak base drugs.
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Absorption of Drugs
1. Sites of absorption through the GI tract 3) Small intestine
a. The primary site for most drugs. b. Large surface area - Folds, villi and microvilli and high blood perfusion rate.

c.

pH = 5-8.

d. Passive diffusion. e. Absorption can also take place by active transport, facilitated diffusion, endocytosis and filtration.

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Absorption of Drugs
1. Sites of absorption through the GI tract
4) Large intestine
a. Not important for drug absorption, if the drug is absorbed effectively in small intestine.

b. Can be a site of absorption for incompletely absorbed drugs.

c.

Less absorption then small intestine less area and solid nature of contents.

d. Rectum can be used for drug administration.

For drugs that cause irritation to the stomach After GI surgery Children Partially avoids liver first pass effect: The half of blood flow goes into
liver, the half of blood flow enters the systemic circulation directly. 30

Absorption of Drugs
2. Factors that modify absorption in the GI tract
1) Drug solubilization 2) Formulation factors 3) Concentration of drug at the absorption site 4) Blood flow at the absorption site 5) Surface area of absorption 6) Route of administration 7) Gastric emptying 8) Food

9) Intestinal motility
10) Metabolism of drug by GI tract
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Absorption of Drugs
2. Factors that modify absorption in the GI tract
Hydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell membrane.

Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids - cannot
gain access to the surface of cells.

- largely hydrophobic yet have some solubility in aqueous solutions

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
1) Drug solubilization breaking drugs into smaller, more
absorbable particles

Solid

disintergration

deaggregation Granules fine particles:

Solution

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
2) Formulation factors materials added to the drug during processing
can affect the solubilization of the drug.

a. Fillers add bulk to the tablet

b. Disintegrators cause tablet to break down into granules

c. Binders hold tablet together d. Lubricants prevent tablet from sticking to machinery
Formulation factors - not clinically important if the drug is absorbed effectively and may have important influence on drug absorption for these drugs which are not effectively absorbed in the GI tract - influence drugs bioavailability.
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Absorption of Drugs
2. Factors that modify absorption in the GI tract
3) Concentration of drug at the absorption site
Passive diffusion Driving force the concentration gradient. The higher the concentration of the drug, the faster the rate of absorption.

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
4) Blood flow at the absorption site - maintain concentration gradient driving force

Membrane

Blood

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
5) Surface area of absorption
small intestine

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
6) Route of administration

GI tract first pass effect

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
7) Gastric emptying
small intestine primary site of drug absorption Anything that delays/accelerates gastric emptying will decrease/increase drug absorption.

For all drugs - acidic, basic or neutral substances.

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
8) Food
High fat food delay gastric emptying slow absorption

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
9) Intestinal motility depends on whether the drug is completely absorbed under
normal condition.
a. Completely absorbed early upon entry into the small intestine, increasing intestinal motility will not significantly affect absorption. b. Not completely absorbed before entry into the small intestine, increasing/decreasing intestinal motility will slow down/facilitate drug absorption.

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Absorption of Drugs
2. Factors that modify absorption in the GI tract
10) Metabolism of drug by GI tract
a. Drug metabolizing enzymes in the GI tract b. Microbes in the GI tract - metabolize certain drugs

- Drug metabolites are not usually absorbed.

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Absorption of Drugs
3. Bioavailability
Fraction of administrated drug that reaches the systemic circulation

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Absorption of Drugs
3. Bioavailability
Determination of Bioavailability

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Absorption of Drugs
4. Other sites of drug administration/absorption.
1). Lung gases, liquid droplets or solid particles
Advantages: The drug can have local effects - Epinephrine for asthma. The drug can have systemic effects - general anesthetics Large surface area, limited thickness of pulmonary membrane and high blood flow allow for almost instant absorption by diffusion Avoid first pass effect Disadvantages: Administration is cumbersome - must use specific machines or equipment Patients must be able to inhale with certain timing and depth in order to get full effects of drug Impaction may occur, if drug particles size is too large to pass through the bronchi and reach the alveoli.
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Absorption of Drugs
4. Other sites of drug administration/absorption
2) Skin Most drugs that are incorporated into creams or ointments are applied to the skin for local effect.
Drug absorption through the skin - Passive diffusion lipid solubility

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Drug Distribution
Transfer of drug from systemic circulation to tissues

Capillary endothelium cells

Blood plasma

Interstitial fluid
Intracellular

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Drug Distribution
1. Factors that affect drug distribution
1) Regional blood flow 2) Capillary permeability 3) Rate of transfer from interstitial fluid into tissues 4) Binding to plasma proteins

2. Barriers to drug distribution

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Drug Distribution
1. Factors affecting distribution:
1) Regional blood flow unequal distribution of cardiac output
Perfusion rate: blood flow to tissue mass ratio
Higher: heart, kidney, liver, lung and brain Moderate: muscle and skin Low: adipose tissue The perfusion rate affects the rate at which a drug reaches the equilibrium in the extracellular fluid of a particular tissue. The greater the blood flow, the more rapid the drug distribution from plasma into interstitial fluid. Therefore, a drug will appear in the interstitial fluid of liver, kidney and brain more rapidly than it will in muscle and skin.
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Drug Distribution
Blood perfusion rates in adult humans
Tissue Perfusion rate (ml/min/100g tissue) Lung 400 Kidney 350 Muscle 5 Skin 5 Adipose tissue 3

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Drug Distribution
1. Factors affecting distribution
2) Capillary permeability
Drug transfer through capillary filtration

a. Capillary structure: Capillary size

Liver: greater filtration potential Brain: lower capillary permeability

Liver slit junction Brain tight junction -blood-brain barrier

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Drug Distribution
Blood-brain barrier

Liver

Brain
Tight junction Passive diffusion Carrier-mediated transport

Slit junction

Lipid soluble drugs Drugs

Endothelial cells

MEMBRANE

MEMBRANE
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Drug Distribution
3) Rate of transfer from interstitial fluid into tissues
Passive diffusion, active transport and endocytosis. Passive diffusion - the most common and quickest means

Blood plasma

Interstitial fluid

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Drug Distribution
4) Binding to plasma proteins - reversible
Capillary endothelium cells

Blood

A + P = AP

Interstitial fluid

Cells and tissues

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Drug Distribution
4) Binding to plasma proteins
a. Consequence of drug binding to plasma proteins:
Cannot go to its receptor at the site of action Cannot be distributed to body tissues Cannot be metabolized by enzymes Cannot be excreted from the body

b. Bound drugs are pharmacologically inactive. c. Drug binding to plasma protein will delay the onset of drug action. d. Drug binding to plasma proteins will decrease the intensity of drug action. e. Drug binding to plasma proteins may prolong drug action.
Reservoir of non-metabolized drug in the body Surmin trypanosomiasis A single IV injection may be effective for three months. Warfarin 97% bound to plasma proteins and 3% free.
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Drug Distribution
4) Binding to plasma proteins
f. Types of plasma proteins: Albumin Lipoproteins alpha1-acid glycoprotein

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More plasma proteins Less free drug available

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Drug Distribution
2. Barriers to drug distribution:
2) Placental transfer
Placenta - Not a barrier most drugs
May have profound affects on fetal development.

3) Blood testicular barrier

Regulates the passage of steriods Prevents chemotherapeutic agents from reaching the testis

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Excretion of Drugs
Drugs are removed from the body or drugs are transferred from the internal to the external environment

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Excretion of Drugs
1. Sites for drug excretion:
1) 2) 3) 4) 5) 6) 7) Kidney - Urine Liver Bile Skin Lung Milk Semen Saliva
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Excretion of Drugs
2. Renal excretion
1) Glomerular filtration Drugs from glomerulus into the renal tubules Pressure blood flow - 20% of blood volume is filtered at the glomerulus Lipid soluble drugs also by passive diffusion Active secretion

Glomerular filtration

Passive Reabsorption
(unionized, lipid soluble)

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Excretion of Drugs
2. Renal excretion
1) 2) Glomerular filtration Active secretion Active transport systems: Organic acids/Anions Organic bases/Cations Relatively non-specific Anion/acid system penicillins, phenobarbital, uric
acid, et al.

Glomerular filtration

Active secretion

Cation/base system morphine,

catecholamines, histamine, et al.

Passive Reabsorption
(unionized, lipid soluble)

In some cases can remove protein-bound drugs from the blood

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Excretion of Drugs
2. Renal excretion
1) 2) 3) Glomerular filtration Active secretion Passive reabsorption

Glomerular filtration

Active secretion

Formation of concentration gradient of drug in tubular filtrate Transfer of unionized, lipid soluble drugs back to the blood by pass diffusion passive reabsorption Excretion of ionized, lipid-insoluble drugs More ionization more secretion pH of urine = 4.5 8

Passive Reabsorption
(unionized, lipid soluble)

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Excretion of Drugs
3. Secretion from the liver:

Liver - Metabolizing enzymes Drugs are filtered from liver capillaries into interstitial fluid liver has larger fenestrae which will allow the filtration of most drugs Drugs in interstitial fluid are transported into hepatocytes by a. Passive diffusion b. Carrier-mediated transport Drugs are actively transported from the hepatocytes into the bile capillaries by 4 active transport systems a. Acids b. Bases c. Neutral compounds d. Bile acids Lipid insoluble or ionized drugs excretion Enterohepatic cycling: Liver Bile intestine
a. b. c. Lipid soluble reabsorption from intestine to bile transport back to the liver Prolong drug action Conserve endogenous substances VD3, B12, folic acid, estrogens.
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Excretion of Drugs
4. Pulmonary excretion
Gasses and volatile liquids Simple diffusion from the blood into the airway

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Excretion of Drugs
5. Sweat and saliva
Drugs or drug metabolites Passive diffusion Drug taste after i.v. administration Side reaction of the skin Examples (saliva): Phenytoin , Clonidine, Diazepam etc. (Sweat ): Rifampicin
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Excretion of Drugs
6. Milk
Passive diffusion

Milk pH 6.5 ion trapping of weak bases

Plasma protein binding decreases drug concentration in milk Not very important for mother, but may be important for infant

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 Some drugs are excreted via the semen. Examples : FENESTERIDE (hair fall treatment) ,Ghloroquine (antimalarial) ,Sulfasalazine (sulphonamides) , verapamil(Calcium channel blocker) ,propranolol , nicotine etc.

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